Synthesis of vitamin E

ABSTRACT

A synthesis of Vitamin E in racemic or optically active forms from 6-methyl-2-hepten-4-ol; 6,10-dimethyl-2-undecen-4-ol or 6-benzyloxy-2,5,7,8-tetramethyl-chroman-2-acetaldehyde including intermediates in this synthesis.

BACKGROUND OF THE INVENTION

In the past, tocopherol and derivatives thereof which have the formula##STR1## and optically active alpha-tocopherol which is the 2R,4'R,8'Risomer of the compound of formula I, i.e., a compound of the formula##STR2## have been prepared through isolation from natural sources suchas vegetable oil. This procedure suffers from many drawbacks due to thefact that the tocopherol content of these oils is very small. Therefore,a great amount of oil must be processed in order to isolate a smallamount of natural tocopherol. Additionally, the process whereby varioustocopherols are isolated from vegetable oil is extremely cumbersome.

Vitamin E active compounds have been synthesized by reacting via Wittigreaction a compound of the formula: ##STR3## wherein R forms with itsattached oxygen moiety an ether protecting group removable byhydrogenolysis or acid catalyzed cleavage; R is preferably benzyl;

And a compound of the formula: ##STR4##

The compound of formula II can be a racemate or a 2R or 2S isomer,depending upon the desired isomeric form of the compound of formula I.

The compound of formula II can also be a racemate or various 2 and 6, Rand S isomers. Where the compound of the formula III has a 2R, 6Rconfiguration, i.e., a compound of the formula ##STR5## then naturalα-tocopherol is produced when the compound of the formula III-A and the2S isomer of the compound of formula II are utilized.

In accordance with this process, it has been desired to provide a simpleand economic method for preparing the compound of formula III and III-A,natural vitamin E and isomers derived therefrom from relatively cheapand economic starting materials.

SUMMARY OF THE INVENTION

In accordance with this invention, it has been found that the compoundof the formula ##STR6## wherein n is an integer from 0 to 1 can beprepared from a compound of the formula ##STR7## wherein n is as above.

The compound of formula V where n is 1 is the compound of formula III.The compound of formula V where n is 0 is compound XXX in Ser. No.544,163 filed Jan. 27, 1975 and its conversion to the compound offormula III above and vitamin E is disclosed in Ser. No. 544,163, whichdisclosure is incorporated by reference.

The compound of formula VI above where n is 0 is the compound of formulaIX-A and IX-B in U.S. Application Ser. No. 544,153 filed Jan. 27, 1975,Chan and Saucy and the compound of formula VI above where n is 1 is thecompound of formula XXIII-A and XXIII-B in U.S. patent application Ser.No. 544,153. The method of preparation for these compounds is disclosedin said U.S. patent application Ser. No. 544,153 which disclosure isincorporated herein by reference.

In accordance with another embodiment of this invention a compound ofthe formula ##STR8## wherein R is as above is converted to a compound offormula I.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this application, the term "lower alkyl" comprehendsboth straight and branched chain saturated hydrocarbon groups containingfrom 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, etc.As used throughout this application, the term "halogen" includes allfour halogens, such as bromine, chlorine, fluorine and iodine. The term"alkali metal" includes sodium, potassium, lithium, etc.

In the pictorial representation of the compounds given throughout theapplication, a ( ) tapered line indicates a substituent which is pointedout of the plane of the paper towards the reader.

The term "lower alkoxy" as used throughout the specification denoteslower alkoxy groups containing from 1 to 7 carbon atoms such as methoxy,ethoxy, propoxy, isopropoxy, etc.

As also used herein the term "aryl" signifies mononuclear aromatichydrocarbon groups such as phenyl, tolyl, etc. which can beunsubstituted or substituted in one or more positions with a loweralkylenedioxy, a halogen, a nitro, a lower alkyl or a lower alkoxysubstituent, and polynuclear aryl groups such as naphthyl, anthryl,phenanthryl, azulyl, etc., which can be unsubstituted or substitutedwith one or more of the aforementioned groups. The preferred aryl groupsare the substituted and unsubstituted mononuclear aryl groups,particularly phenyl. The term "aryl lower alkyl" comprehends groupswherein aryl and lower alkyl are as defined above, particularly benzyl.The term "aroic acid" comprehends acids wherein the aryl group isdefined as above. The preferred aroic acid is benzoic acid.

The term "ether protecting group removable by acid catalyzed cleavage"designates any ether which, upon acid catalyzed cleavage orhydrogenolysis yields the hydroxy group. A suitable ether protectinggroup is, for example the tetrahydropyranyl ether or4-methyl-5,6-dihydro-2H-pyranyl ether. Others are arylmethyl ethers suchas benzyl, benzhydryl or trityl ethers or alpha-lower alkoxy lower alkylether, for example, methoxymethyl or allylic ethers, or trialkyl silylethers such as trimethyl silyl ether or dimethyl-tert.-butyl silylethers. Other ethers which are preferred are tertiary butyl ethers.

The preferred ethers which are removed by acid catalyzed cleavage aret-butyl and tetrahydropyranyl. Acid catalyzed cleavage is carried out bytreatment with a strong organic or inorganic acid. Among the preferredinorganic acids are the mineral acids such as sulfuric acid, hydrohalicacid, etc. Among the preferred organic acids are lower alkanoic acidssuch as acetic acid, trifluoroacetic acid, etc. and arylsulfonic acidssuch as para-toluenesulfonic acid, etc. The acid catalyzed cleavage canbe carried out in an aqueous medium or in an organic solvent medium.Where an organic acid is utilized, the organic acid can be the solventmedium. In the case of t-butyl, an organic acid is generally utilizedwith the acid forming the solvent medium. In the case oftetrahydropyranyl ethers, the cleavage is generally carried out in anaqueous medium. In carrying out this reaction, temperature and pressureare not critical and this reaction can be carried out at roomtemperature and atmospheric pressure.

The preferred ethers which are removable by hydrogenolysis are the arylmethyl ethers such as benzyl or substituted benzyl ethers. Thehydrogenolysis can be carried out by hydrogenation in the presence of asuitable hydrogenation catalyst. Any conventional method ofhydrogenation can be utilized in carrying out this procedure. Anyconventional hydrogenation catalyst such as palladium or platinum can beutilized.

In accordance with this invention the compound of formula VI isconverted to the compound of formula V via th following intermediates:##STR9## wherein R₁, R₂ and R₃ are lower alkyl and n is as above.

In the reaction of a compound of the formula V to produce a compound ofthe formula X, the compound of formula VI is reacted with a compound ofthe formula ##STR10## wherein R₁ and R₂ are as above, and R'₁ is loweralkyl.

The reaction of the compound of formula V with the compound of formulaXIV is carried out via a rearrangement. In carrying out this reaction,temperatures of from 100° C. to 400° C. are utilized with temperaturesof about 150° C. to 250° C. being preferred. This reaction is carriedout in an inert organic solvent medium. Among the preferred solvents arethe hydrocarbon solvents such as the aliphatic and aromatic hydrocarbonswhich have a boiling point of at least 100° C. Any conventional inerthydrocarbon solvent having a boiling point of at least 100° C. can beutilized in carrying out this reaction. Among the preferred solvents arethe aromatic hydrocarbon solvents such as toluene, xylene, benzene, etc.However, aliphatic hydrocarbon solvents such as octane, hexane, etc. canbe utilized in carrying out this reaction. Aliphatic and aromatic aminessuch as n-tributylamine, collidine, etc. having a boiling point of atleast 100° C. can also be used.

The reaction of the compound of formula VI with a compound of theformula XIV produces the rearranged product of formula X.

The compound of formula X is converted to the compound of formula XI byhydrogenation in the presence of a conventional hydrogenation catalyst.Any of the methods of conventionally reducing a double bond to a singlebond can be utilized. Among the preferred methods for carrying out thisreaction is by hydrogenation in the presence of hydrogenation catalystssuch as palladium or platinum. In carrying out this reaction,temperature and pressure are not critical and this hydrogenation can becarried out at room temperature and atmospheric pressure. On the otherhand, elevated temperatures and pressures can be utilized.

The compound of formula XI is converted to the compound of formula XIIby hydrolysis. Any conventional method of hydrolyzing an amide can beutilized in carrying out this reaction. Among the preferred methods isby treating the amide with an aqueous inorganic acid such as aqueoushydrochloric acid. In carrying out this reaction, temperature andpressure are not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. On the other hand, elevatedtemperatures can be utilized.

The compound of formula XII is converted to the compound of formula XIIIby esterification. Any conventional method of esterification can beutilized to carry out this reaction. Where R₃ is a methyl group, theesterification is carried out under conventional conditions usingdiazomethane. On the other hand, where it is desired that R₃ be a loweralkyl group of from 2 to 7 carbon atoms, the esterification is performedin the conventional manner by reacting a reactive derivative such as ahalide or anhydride of the compound of the formula XII with an alcohol.

The compound of formula XIII is converted to the compound of the formulaV by reduction. Any conventional method of reducing an ester group tothe corresponding alcohol can be utilized. Among the preferred methodsof reduction is treating the compound of formula XIII with an aluminumhydride reducing agent. Any of the conventional aluminum hydridereducing agents such as lithium aluminum hydride or diisobutyl aluminumhydride can be utilized in this reaction. Among the other preferredreducing agents are the alkyl aluminum hydride reducing agents such asdiisoamyl aluminum hydride, etc., as well as sodiumdihydrobis[2-methoxyethoxy]-aluminum hydride. The reduction with analuminum hydride reducing agent is carried out in an inert organicsolvent medium. Any conventional inert organic solvent medium can beutilized for carrying out this reaction. Among the preferred inertorganic solvents are included pentane, dioxane, diethyl ether, hexane,toluene, benzene or xylene. Generally, temperatures of from about -120°C. to about 150° C. are utilized in carrying out this reductionreaction.

Where it is desired to produce an opticaly active compound of theformula III-A which is an intermediate for optically active vitamin E,one starts with the compound of formula III in the following isomericform ##STR11## wherein n is as above; one of R₁₀ and R₁₁ is hydrogen andthe other is hydroxy with the proviso that when R₁₀ is hydroxy, the 2-3double bond is a cis configuration and when R₁₁ is hydroxy, the 2-3double bond has a trans configuration

to produce an optically active compound of the formula ##STR12## whereinR₁ , R₂ and n are as above.

In accordance with this invention it has been found that when a compoundof the formula VI-A is reacted in the aforementioned manner with acompound of the formula XIV, the optically active compound of formulaX-A is produced. Therefore, it has been found that the rearrangement,which occurs when a compound of formula VI-A is utilized as a startingmaterial and is reacted with a compound of the formula XIV occursasymmetrically to produce a compound of formula X-A which can beconverted to optically active natural α-tocopherol of formula I-A. Thesame optical configuration in the compound of formula X-A is maintainedthroughout its conversion to produce an optically active isomer of thecompound of the formula V, i.e., a compound of formula ##STR13## whereinn is as above via intermediates of the formulas ##STR14## wherein R₁, R₂and n are as above.

In accordance with another embodiment of this invention, a compound ofthe formula VIII is converted to a compound of formula I via thefollowing intermediates: ##STR15## wherein R, R₁, R₂ and R₃ are asabove; and R₁₂ is a leaving group.

The compound of formula VIII is reacted with the compound of the formulaXIV to produce the rearrangement product of formula XX in the samemanner as described in connection with the reaction of a compound of theformula XIV with a compound of the formula VI to form a compound of theformula X.

The compound of the formula XX is converted to the compound of theformula XXI in the same manner as described in connection with theconversion of a compound of the formula X to XI. In this conversion,care must be taken that approximately one mole of hydrogen is utilizedper mole of the compound of the formula XX so as not to remove the ORmoiety where the OR moiety forms an ether group removable byhydrogenolysis. The use of one mole of hydrogen per mole of the compoundof formula XX will hydrogenate the double bond without effecting the ORmoiety where R forms an ether group removable by hydrogenalysis. In thecase, where higher molar ratios of hydrogen are utilized, the hydrogenwill attack the OR group forming the corresponding alcohol.

The compound of formula XXI is converted to the compound of formula XXIIin the same manner described in connection with the conversion of acompound of the formula XI to a compound of the formula XII. Thecompound of formula XXII is converted to compound of the formula XXIIIin the same manner as described in connection with the conversion of acompound of the formula XII to a compound of the formula XIII.

Either the compound of the formula XII or the compound of the formulaXXIII can be converted to a compound of the formula XXIV by reductionwith a lithium aluminum hydride reducing agent in the same manner asdescribed hereinbefore with respect to the conversion of a compound ofthe formula XIII to a compound of the formula V.

The compound of formula XXIV is converted to the compound of formula XXVby converting the hydroxy group in the compound of formula XXIV to aleaving group. Any conventional method of converting a hydroxy group toa leaving group can be utilized in this reaction. Among the preferredleaving groups formed by--OR₁₂ are alkyl sulfonyloxy such as methodsulfonyloxy or other lower alkyl sulfonyloxy groups; aryl sulfonyloxysuch as p-toluene-sulfonyloxy, naphthyl sulfonyloxy, etc.

The compound of formula XXV is converted to the compound of formula I byreacting the compound of formula XXV with a compound of the formula:##STR16## wherein X is halogen; followed by hydrogenalysis or acidhydrolysis to remove the RO-group. The reaction of the compound offormula XXV with a compound of formula XVI is carried out with adi(alkali metal)tetrahalocuprate utilizing the procedure of Fouquet andSchlosser on pages 82 and 83 of Angew Chem International Edit, Vol. 13,1974. In this procedure, carbon to carbon linkage of hydrocarbons iscarried out through the reaction of a magnesium halide with a sulfonylester. In accordance with this invention, it has been discovered thatthis reaction can be carried out with an ether or chromane functionalgroup so that the sulfonyl ester can carry these functional groups. Inaccordance with this invention, it has been discovered that the ether orchromane groups do not interfere with this reaction. In this reaction,any conventional di(alkali metal) tetrahalocuprate can be utilized withdilithium tetrachlorocuprate being preferred. Generally, this reactionis carried out in the presence of an ether solvent. Any conventionalinert organic ether solvent can be utilized. Among the preferredsolvents are included tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane, diglyme, etc. In carrying out this reaction,temperature and pressure are not critical and this reaction can becarried out at room temperature and atmospheric pressure.

In accordance with a preferred embodiment of this invention, thecompound of formula I-A, i.e., optically active natural α-tocopherol canbe prepared through the discovery that the rearrangement of an opticallyactive form of the compound of formula VIII with a compound of formulaXIV occurs stereoselectively so that the optical isomer convertible tonatural α-tocopherol is produced. Hence in accordance with thisinvention, we have found that when the optically active form of thecompound of formula VIII which has the formula ##STR17## wherein R is asabove and one of R'₁₀ and R'₁₁ is hydroxy and the other is hydrogen withthe proviso that when R'₁₀ is hydroxy the 2-3 double bond is cis andwhen R'₁₀ is hydrogen, the 2-3 double bond is trans is utilized, acompound of formula I-A is produced.

The compound of formula VIII-A is reacted in the aforementioned mannerwith a compound of the formula XIV to produce a compound of the formula##STR18## wherein R, R₁ and R₂ are as above. The compound of formulaXX-A is converted to the optically active form of the compound offormula XXV, i.e., a compound of the formula ##STR19## wherein R and R₁₂are as above in the manner described hereinbefore via the followingcompounds: ##STR20##

The compound of formula XXV-A, when reacted with the optically activeform of the compound of formula XVI, i.e., ##STR21## wherein X is asabove via a Grignard reaction produces the compound of formula I-A inthe same manner as described in connection with the reaction of acompound of formula XXV with a compound of formula XVI to produce acompound of formula I.

The compound of formula VIII is formed from a compound of formula II byreaction via a Grignard reaction with a compound of the formula

    CH.sub.3 --C.tbd.CMgBr                                     XXIX

to produce a compound of the formula ##STR22## where R is as above;which when subjected to selective hydrogenation or metal hydridereduction produces the compound of formula VIII.

On the other hand, when an optical isomer of the formula II having theformula: ##STR23## wherein R is as above; is condensed with the compoundof formula XXIX, a mixture is formed containing a compound ##STR24## anda compound of the formula ##STR25## wherein R is as above. The compoundof formula XXX-A can be converted to a compound of the formula ##STR26##where R is as above and Δ indicates that a double bond has a cisconfiguration. The compound of formula XXX-B can be converted to acompound of the formula ##STR27## wherein R is as above and Δ' indicatesthat the double bond has a trans configuration.

The mixture of the compound of formula XXX-A and XXX-B can be separatedby any conventional means such as crystallization.

The compound of formula XXX-A is converted to the compound of theformula VIII-A₁ by hydrogenation in the presence of a selectivehydrogenation catalyst. Any conventional catalyst which selectivelyreduces only the triple bond (acetylenic linkage) to a double bond canbe utilized in carrying out this conversion. Among the preferredselective hydrogenation catalysts are the palladium catalysts whichcontain a deactivating material such as lead, lead oxide or sulfur.Among the preferred selective hydrogenation catalysts are included thepalladium/lead catalyst of the type disclosed in Helvetica ChemicaActa.: 35, page 446 (1952) and U.S. Pat. No. 2,681,938, Lindlar. Incarrying out this hydrogenation, temperature is not critical and thisreaction can be carried out at room temperature. On the other hand,elevated or reduced temperatures can be utilized. Generally, thisreaction is carried out in an inert organic solvent. Any conventionalinert organic solvent can be utilized such as n-hexane, ethyl acetate,toluene, petroleum ether or methanol. The selective hydrogenation of acompound of the formula XXX-A utilizing a selective hydrogenationcatalyst produces a cis configuration across the double bond formed inthe compound of formula VIII-A₁ . Therefore, the subjection of acompound of the formula XXX to catalytic selective hydrogenationproduces a compound of the formula VIII-A₁ where the double bond is acis double bond.

In accordance with this invention, the compound of formula XXX-B isconverted to the compound of VIII-A₂ by chemical reduction with analuminum hydride reducing agent. The chemical reduction of the compoundof formula XXX-B reduces the triple bond to a double bond which has atrans configuration. Hence, the compound of formula VIII-A is formed bythis chemical reduction with the double bond having a transconfiguration. The reduction can be carried out by treating the compoundof formula XXX-B with an aluminum hydride reducing agent in the mannerdescribed hereinbefore. Any of the conventional aluminum hydridereducing agents such as those described hereinbefore can be utilized tocarry out this reduction reaction.

The following Examples are illustrative but not limitative of theinvention. All temperatures are in degrees Centigrade (° C.) and theether utilized is diethyl ether. The term "5% palladium on carbon"designates a carbon catalyst containing 5% by weight palladium and 95%by weight carbon. The term "Lindlar catalyst" designates a catalystprepared from palladium, calcium carbonate and lead acetate as describedin Organic Synthesis Collective Volume 5: pages 880-883 (1973). In theExamples, the percent R and S were determined by nmr.

EXAMPLE 1 Preparation of 2(R,S,)-6-dimethyl-3(E)-heptenoic aciddimethylamide

6-methyl-2(Z)-hepten-4(R,S)-ol (1.28 g., 10 mmol) and dimethylformamidedimethyl acetal (7.14 g., 60 mmol) in xylene (20 ml.) were refluxed at130° C. under the continuous removal of methanol for 20 hours. Afterevaporation of xylene in a rotary evaporator at 42°/20 mm Hg, the crudeoily product was chromatographed on 40 g. of silica gel. Elution withdiethyl ether = petroleum ether (30°-60°) (1:3 parts by volume) gave 540mg. (42.1% by weight) of starting material. Further elution with ether =petroleum ether (11 = 9 parts by volume) afforded 257 mg. of crudeproduct, which on Kugelrohr distillation at 65°-70° C./0.2 mm Hg yielded200 mg. (18.9%) based on recovered starting material) of2(R,S),6-dimethyl-3(E)-heptenoic acid dimethylamide as a colorless oil.

EXAMPLE 2 Preparation of 2(R),6-dimethyl-3(E)-heptenoic aciddimethylamide from 6-methyl-2-(Z)-hepten-4(R)-ol

Optically active 6-methyl-2-(z)-hepten- 4(R)-ol (2.56 g., 20 mmol)(having about 96.5% by weight R and about 3.5% by weight S),dimethylformamide dimethylacetal (15 g., 0.126 mmol) in xylene (40 ml.)were refluxed under continuous removal of methanol for 120 hours. Thesolvent and excess of reagent were evaporated off in a rotary evaporatorat 55° C./12-20 mm Hg. to give 3.12 g. of light brown colored oil. Thiswas purified by chromatography on 100 g. of silica gel. Elution withether = petroleum ether (1:3 parts by volume) afforded 1.796 g. of2(R)-6-dimethyl-3(E)-heptenoic acid dimethylamide (49.0% yield).

EXAMPLE 3 Reaction of 6-methyl-2(E)-hepten-4(S)-ol withdimethylformamide dimethyl acetal

1.28 g. (10 mmol) of 6-methyl-2(E)-hepten-4(S)-ol (having 97.8% byweight S and about 2.2% by weight R) and 7.5 g. of dimethylformamidedimethyl acetal in 20 ml. of xylene were refluxed (124°-126° C.) for 70hours under continuous removal of methanol. The solvent and excess ofreagent were evaporated off at 60° C/0.20 mm Hg and the crude productwas chromatographed on 30 g. of silica gel. Elution with ether =petroleum ether (1:4 parts by volume) gave 1.479 g. ofbeta-gamma-unsaturated amide. This was further purified by evaporativedistillation to give a mixture containing 87.2% by weight of2(R),6-dimethyl-3(E)-heptenoic acid dimethylamide and 12.8% by weight of3(S),6-dimethyl-3(Z)-heptenoic acid dimethylamide (determined by nmr) asa colorless oil [α]_(D) ²⁵ -46.37° (c 5.0215, CHCl₃).

EXAMPLE 4 Preparation of 2(R),6-dimethylheptanoic acid dimethylamide

1.20 g. of 2(R),6-dimethyl-3(E)-heptenoic acid dimethylamide (95%R, 5%S) was hydrogenated in 50 ml. of ethylacetate at 220° C. in the presenceof 120 mg. of 5% by weight palladium on 95% by weight charcoal. After4.0 hours, no more hydrogen was absorbed and the catalyst was filteredoff and washed with 50 ml. of ethyl acetate. The solvent was evaporatedoff to give 1.21 g. of colorless oil. This was distilled by evaporationat 82°-89° C,/0.15 mm Hg. to yield 1.191 g. of pure2(R),6-dimethylheptenoic acid dimethylamide, [α]_(D) ²⁵ -27.14° (c5.1148, CHCl₃).

EXAMPLE 5

From 1.10 g. of 2(R),6-dimethyl-3(E)-heptenoic acid dimethylamide (87.2%R, 12.8% S) and 110 mg. of 5% by weight palladium on 95% by weightcharcoal, in 50 ml. of ethylacetate was hydrogenated at 23° C. andatmospheric pressure for 3.0 hours to give 1.07 g. of colorless oil,b.p. 83° C/0.13 mm Hg (Kugelrohr), [α]_(D) ²⁵ -21.61° (C 5.0753, CHCl₃),nmr revealed a mixture of 84.6% by weight 2(R),6-dimethylheptanoic aciddimethylamide and 12.8% by weight 2(S),6-dimethyl-heptanoic aciddimethylamide.

EXAMPLE 6 Preparation of 2(R),6-dimethylheptanoic acid

538 mg. of 2(R),6-dimethylheptenoic acid and dimethylamide fro Example 4in concentrated aqueous hydrochloric acid (10 ml.) was refluxed withstirring for 20 hours. After evaporating off the concentrated HCl at45°-50° C./15-20 mm Hg, the oily residue was taken into 10% by weightaqueous NaOH. The aqueous phase was extracted with 3 × 20 ml. ether. Thecombined ether extract was washed with water, dried (MgSO₄) andevaporated to dryness to give 10 mg. of neutral material. The alkalineaqueous phase was then cooled in an ice-bath, and acidified withconcentrated aqueous hydrochloric acid to Congo red. This was extractedwith ether (3 × 50 ml.). The combined ether extract was washed withwater, dried (MgSO₄) and evaporated to give 375 mg. (81.5% yield) ofoil. Distillation (evaporative) at 82°-86° C./0.15 mm Hg gave 365 mg. of2(R),6-dimethyl heptanoic acid as a colorless oil, [α]_(D) ²⁵ =15.60° (c4.9232, CHCl₃).

EXAMPLE 7

462 mg. of 2(R),6-dimethylheptanoic acid dimethylamide [α]_(D) ²⁵-21.61°, from Example 5 was refluxed with stirring in concentratedhydrochloric acid (10 ml.) for 20 hours. It was worked up as in Example6 to give 248 mg. of colorless oil, b.p. 92°-95° C./0.20 mm Hg.(Kugelrohr), [α]_(D) ²⁵ -12.80° (c. 5.0408, CHCl₃) which was a mixturecontaining 84.6% by weight 2(R),6-dimethylheptanoic acid and 12.4% byweight 2(S),6-dimethylheptanoic acid.

EXAMPLE 8 Preparation of 2(R),6-dimethylheptanoic acid methyl ester

2(R),6-dimethylheptanoic acid (300 mg. [α]_(D) ²⁵ -15.6°, for Example 6was dissolved in ether and treated with an excess of etheraldiazomethane. The yellow solution was left at 23° C. overnight.Evaporation of ether (45°/20 mm Hg) to dryness gave 260 mg. of2(R),6-dimethylheptanoic acid methyl ester, b.p. 114°-119°/45 mm Hg.(evaporative distillate), [α]_(D) ²⁵ -20.10° (c. 1.1242, CHCl₃).

EXAMPLE 9

In a similar manner, 2(R),6-dimethylheptenoic acid (from Example 7,[60]_(D) ²⁵ -12.80°) was converted to a mixture containing 85% by weightof 2R,6-dimethylheptanoic acid methyl ester and 15% by weight of2(S),6-dimethylheptanoic acid methyl ester (as determined by nmr).

EXAMPLE 10 Preparation of 2(R),6-dimethylheptanol-1

2(R),6-dimethylheptanoic acid and methyl ester (105 mg., [α]_(D) ²⁵-20.10°, from Example 8) and 100 mg. of LiAlH₄ in 15 ml. of ether wererefluxed with stirring for 2 1/2 hours. The reaction was cooled in anice-bath and the excess of LiAlH₄ was destroyted by carefully addingwater followed by 20 ml. of cold 2 N aqueous sulfuric acid. It was thenextracted with ether (3 × 50 ml.) and combined ether extract was washedwith water and dried (MgSO₄). Evaporation of ether to dryness anddistillation of the crude product afforded 65 mg. of2(R),6-dimethyl-heptanol-1 as a colorless oil, b.p. 130°/30 mm Hg.(evaporative distillate) [α]_(D) ²⁵ + 9.23° (c 1.1049, benzene).

EXAMPLE 11

6(R),10-dimethyl-2(Z)-undecen-4(R)-ol (1.54 g., 7.77 mmol) (having about91.8% by weight R, and about 8.2% by weight S) and dimethylformamidedimethyl acetal (7.0 g., 58.8 mmol) in xylene (15 ml.) were refluxed at124°-126° C. under continuous distillative removal of methanol for 93hours. The xylene was evaporated off at reduced pressure and the crudeproduct (2.20 g.) was chromatographed on 40.0 g. of silica gel. Elutionwith ether = petroleum ether (1:4 parts by volume) gave 0.815 g. ofproduct (41.4% yield). This was distilled (evaporative distillation) at116°-119°/0.15 mm Hg. to give pure2(R),6(R),10-N,N-pentamethyl-3(E)-undecen-amide [α]_(D) ²⁵ -43.70°.

EXAMPLE 12

1.45 g. (7.32 mmol) of 6(R),10-dimethyl-2(E)-undecen-4(S)-ol (havingabout 95% by weight S and 5% by weight R at C₄) and 7.0 g. ofdimethylformamide dimethyl acetal in 15 ml. of xylene were refluxed for93 hours as described in Example 11. The crude product waschromatographed on 40 g. of silica gel and elution with ether/petroleumether (3:17 parts by volume) gave 1.22 g. (65.9% yield) of2(R),6(R),10-N,N-pentamethyl-3(E,Z)-undecenamide after evaporationdistillation, b.p. 138°-142°/0.22 mm Hg. [α]_(D) ²⁵ -30.5° (c 4.9305,CHCl₃).

EXAMPLE 13 Preparation of 2(R),6(R),10-N,N-pentamethylundecanamide

2(R),6(R),10-N,N-pentamethyl-3(E)-undecenamide (636 mg.) and 75 mg. of5% by weight palladium on 95% by weight charcoal in 25 ml. of ethylacetate were hydrogenated at 23° C., 1 atmosphere for 4.0 hours. It wasworked up in the manner of Example 4 and the product was distilled(evaporative distillation at 140°/0.5-0.7 mm Hg. to give 607 mg. of2(R),6(R),10-N,N-penta-methyl-undecanamide as a colorless oil, [α]_(D)²⁵ -15.32° (C 5.2345, CHCl₃).

EXAMPLE 14 Preparation of 2(R),6(R),10-trimethylundecanoic acid

2(R),6(R),10-N,N-pentamethylundecanamide (415 mg., [α]_(D) ²⁵ -15.32°)was refluxed with stirring in concentrated hydrochloric acid (10 ml.)for 24 hours. The reaction mixture was worked up as in Example 6 and thecrude product was distilled (evaporate distillation) at 135°/0.15 mm Hg.to give 305 mg. of 2(R),6(R),10-trimethylundecanoic acid (82% yield) asa colorless oil, [α]_(D) ²⁵ -8.64° (c 4.8382, CHCl₃).

EXAMPLE 15 Preparation of 2(R),6(R),10-trimethylundecanoic acid methylester

2(R),6(R),10-trimethylundecanoic acid (270 mg., [α]_(D) ²⁵ -8.64°) wasdissolved in ether and treated with an excess of etheral soluton ofdiazomethane at 23° C. for 2.0 hour. The crude product was subjected toevaporative distillation at 98°-101°/0.15 mm Hg to give 247 mg. of2(R),6(R),10-trimethylundecanoic acid methyl ester as a colorless oil,[α]_(D) ²⁵ -11.30° (c 1.1065, CHCl₃).

EXAMPLE 16 Preparation of 2(R),6(R),10-trimethylundecan-1-ol

2(R),6(R),10-trimethylundecanoic acid methyl ester (172 mg., [α]_(D) ²⁵-11.30°) and lithium aluminum hydride (170 mg.) in absolute ether (20ml.) were refluxed with stirring for 2 1/2 hours. The reaction mixturewas cooled in an ice-bath and excess of hydride was destroyed bycarefully adding water followed by 30 ml. of 1 N aqueous H₂ SO₄. Theaqueous phase was extracted with ether (3 × 40 ml.) and the combinedether extract was washed with water (3 × 30 ml.) and dried (MgSO₄). Thecrude product (155 mg.) was purified by evaporative distillation to give152 mg. (100% yield) of 2(R),6(R),10-trimethylundecan-1-ol as acolorless liquid, b.p. 100°-102° C./0.08 mm Hg.; [α]_(D) ²⁵ + 6.09° C.(c 2.0366, hexane).

EXAMPLE 17 Preparation of5-[2(S),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S),N,N-trimethyl-3(E)-pentenamide

2(S)-[2'(S)-hydroxy-3(Z)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman(1.0 g., 2.63 mmol, [α]_(D) ²⁵ -30.57°) and dimethylformamide dimethylacetal. (2.2 g., 18.41 mmol) in xylene (10 ml.) were refluxed (130°-135°C.) under the continuous removal of methanol by distillation for 66hours. The solvent and excess of reagent were removed in a rotaryevaporator to give approximately 1.22 g. of brown colored viscous oil,which was purified by column chromatography on 40 g. of silica gel.Elution with ether = petroleum ether (1 = 9) gave 487 mg. of oil.

Further elution with ether = petroleum (55 = 45 parts by volume) thengave 520 mg. of5-[2(S),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S),N,N-trimethyl-3(E)-pentenamideas a light yellow colored viscous oil, (45.5% yield) [α]_(D) ²⁵ + 53.27°(c 3.634, CHCl₃).

EXAMPLE 18

2(S)-[2'(R)-hydroxy-3(E)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman(1.09 g. [α]_(D) ²⁵ - 24.02°) and dimethylformamide dimethyl acetal (2.2g) in xylene (15 ml.) were refluxed for 62 hours as described in Example17. The crude product was purified by chromatography on 30 g. of silicagel. Elution with ether - petroleum ether (1:1 parts by volume) gave 876mg. (76.8% yield) of5-[2'(S),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-N,N-trimethyl-3(E)-pentenamideas a light yellow viscous oil, [α]_(D) ²⁵ + 43.94°.

EXAMPLE 19 Preparation of2(S)-[2(R)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxy-chromanand 2(S)-[2(S)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychroman

To an excess of propynyl magnesium bromide (approximately 2.5equivalents) in 1.0 l. of dry ether was added 64 g. (0.189 mol) of(S)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetaldehyde in 1.0 l. ofdry ether, at 0°-4° C. with mechanical stirring. When addition wascomplete the reaction mixture was further stirred at 0° C. for 1/2 hourand then at 25° C. for 1/2 hour. The reaction mixture was poured insmall portions into 500 ml. of saturated aqueous NH₄ Cl solution. It wasextracted with diethyl ether (4 × 250 ml.). The combined ether extractwas washed with water (3 × 200 ml.), dried over MgSO₄ and concentratedat reduced pressure. Crystallization of the crude product from diethylether - petroleum ether (30° - 60° C.) yielded 27.5 g. of2(S)-[2(R)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychroman,m.p. 89°-91° C., [α]_(D) ²⁵ -16.05° (CHCl₃).

The mother liquor from above was concentrated to dryness andcrystallized from ether - hexane to give 5.01 g. of2(S)-[2(S)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychroman aswhite crystals, m.p. 74°-76° C. [α]_(D) ²⁵ -42.01°.

EXAMPLE 20 Preparation of2(S)-[2(R)-hydroxy-3(E)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman

To a solution of 5.0 g. (13.32 mmol) of2(S)-[2(R)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxy-chromanin 50 ml. of dry ether was carefully added 4.06 ml. of sodiumbis(2-methoxyethoxy)-aluminum hydride (29 mg. - atm. of hydrogen) in 10ml. of dry ether. The resulting solution was refluxed under Argon for 17hours. The solution was cooled in an ice bath and 10% by volume aqueousH₂ SO₄ solution (100 ml.) was carefully added. It was filtered, washedwith ether and water. The aqueous phase was again extracted with ether(3 × 100 ml.). The combined ether phase was washed with saturatedaqueous NaHCO₃ solution (3 × 50 ml.) and water (3 × 50 ml.) and driedover MgSo₄. Evaporation of ether to dryness at reduced pressure yielded5.206 g. of crude product which was crystallized from petroleum ether(b.p. 30°-60° C.) to give 4.23 g. of 2(S)-[2(R)-hydroxy-3(E)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychromanas white needles, m.p. 68°-70° C. [α]_(D) ²⁵ -24.02° (CHCl₃).

EXAMPLE 21 Preparation of2(S)-[2(S)-hydroxy-3(Z)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman

2.5 g. of2(S)-[2(S)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychromanand 0.25 g. of Lindlar catalyst in 15 ml. of ethyl acetate-hexane (2 = 1parts by volume) containing 0.1 ml. of quinoline was hydrogenated at 25°C. and atmospheric pressure. The catalyst was filtered off and washedwith ethyl acetate. The ethyl acetate solution was washed with 1.0 Naqueous HCl (3 × 50 ml.), dried over MgSO₄ and concentrated in vacuo togive 2.508 g. of crude product. Crystallization of this material frompentane yielded 2.053 g. of2(S)-[2(S)-hydroxy-3(Z)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychromanas white crystalls, m.p. 84°-86° C. [α]_(D) ²⁵ -30.57° (CHCl₃).

EXAMPLE 22 Preparation of5-[2(R),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanoicacid

5-[2(S),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S),N,N-trimethyl-3(E)-pentenamidewas hydrogenated with 5% by weight palladium on 95% by weight charcoalas described in Example 5 to give 5-[2(R),6,benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanoic aciddimethylamide. This was refluxed with KOH in ethylene glycol for 17hours and worked up in the manner described in Example 6 to give5-[2(R),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanoicacid.

EXAMPLE 23 Preparation of5-[2(R),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanol-1-and5-[2(R),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanolp-toluenesulfonate

5-[2(R),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanoicacid was reduced to5-[2(R),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanol-1withlithium aluminum hydride as described in Example 10. This material (0.01mol) was dissolved in dry pyridine (30 ml.) and cooled in an ice-bath.To the solution was added 0.02 mol. of p-toluenesulfonyl chloride inportions. The resulting mixture was kept at 0° C. for 20 hours thentreated with ice-water. The precipitated oily material was extractedwith ether and the ether extracts were combined, washed with cold 1 Naqueous HCl, saturated aqueous NaHCO₃, and water, then dried overanhydrous K₂ CO₃ -Na₂ SO₄. After filtration and removal of solvent invacuo, there was obtained5-[2(R),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanolp-toluenesulfonate as a yellow oil.

EXAMPLE 24 (2R,4'R,8'R)- α-tocopheryl benzyl ether

A solution of 3(R),7-dimethyloctyl magnesium bromide (10 mmol) in drytetrahydrofuran (20 ml.) was added dropwise, with stirring to a solutionof 5-[2(R),6-benzyloxy-2,5,7,8-tetramethyl-2-chromanyl]-2(S)-methylpentanol p-toluenesulfonate (7.7 mmol) in tetrahydrofuran(10 ml.) cooled to -78° C. After the addition of 0.4 ml. of 0.1 Mdilithium tetrachlorocuprate solution in tetrahydrofuran, the reactionmixture was stirred for 10 minutes at -78° C, then for 2 1/2 hours at0°-5° C. and finally at 23° C. for 17 hours. Aqueous 1 N H₂ SO₄ wasadded and the mixture was extracted with ether. The combined etherextract was washed with water and dried over anhydrous MgSO₄.Evaporation of ether to dryness in vacuo gave (2R,4'R,8'R)-α -tocopherylbenzyl ether as a viscous oil.

EXAMPLE 25 (2R,4'R,8'R)- α-tocopherol

(2R,4'R,8'R)-α -tocopherol benzyl ether (5 mmol) was hydrogenated in 50ml. of ethyl acetate at 23° C, atmospheric pressure, in the presence of1.0 g. of 5% by weight palladium on 95% by weight carbon catalyst. Afterthe uptake of hydrogen stopped, the catalyst was filtered off and washedwell with ethyl acetate. The solvent was concentrated in vacuo to give(2R,4'R,8'R)- α -tocopherol as a colorless, viscous oil, shown to beidentical with an authentic sample.

We claim:
 1. A process for producing a compound of the formula ##STR28## wherein R is benzyl, trialkyl silyl, t-butyl, benzhydryl, trityl, tetrahydropyranyl, alpha-lower alkoxy-lower alkyl; and R₁ and R₂ are lower alkyl;comprising reacting at a temperature of from 100° C to 400° C in an inert organic solvent medium a compound of the formula: ##STR29## wherein R is as above; with a compound of the formula: ##STR30## wherein R₁ and R are as above; and R₁ ' is lower alkyl.
 2. The process of claim 1 wherein a compound of the formula ##STR31## wherein R is as above; one of R₁₀ and R₁₁ is hydroxy and the other is hydrogen; with the proviso that when R₁₀ is hydroxy, the 3-4 double bond is cis and when the R₁₀ is hydrogen, the 3-4 double bond is trans; is reacted with a compound of the formula: ##STR32## wherein R₁ ', R₁ and R₂ are as above; to produce a compound of the formula: ##STR33## wherein R, R₁ and R₂ are as above. 